CARDIOPROTECTIVE EFFECTS OF THE NOVEL ADENOSINE-A(1) ADENOSINE-A(2) RECEPTOR AGONIST AMP-579 IN A PORCINE MODEL OF MYOCARDIAL-INFARCTION

This study examined the cardioprotective effects and pharmacology of t he novel adenosine A(1)/A(2) receptor agonist -thienyl)-1-methyl-propy l]amino]-3H-imidazo[4,5-b] pyridyl-3-yl] cyclopentane carboxamide) (AM P 579), in a model of myocardial infarction. Experiments were performe d in pentobarbital-anesthetized pigs in which myocardial infarction wa s induced by a 40-min occlusion of the left anterior descending corona ry artery, followed by 3 hr of reperfusion. This procedure resulted in approximately 20% of the left ventricle being made ischemic in all te st groups. In untreated animals, an infarct size equal to 56 +/- 5% of the ischemic area was observed. Preconditioning, with two cycles of 5 min of ischemia followed by 10-min reperfusion, resulted in a 70% red uction in infarct size (17 +/- 5%) relative to risk area. Administrati on of AMP 579 30 min before ischemia (3 mu g/kg i.v. followed by 0.3 m u g/kg/min i.v. through 1 hr of reperfusion) did not change blood pres sure, HR or coronary blood flow but resulted in marked cardioprotectio n: a 98% reduction in infarct size (1 +/- 1%) relative to risk area. M oreover, whereas approximately 90% of control pigs suffered ventricula r fibrillation during ischemia, no fibrillation was observed in animal s treated with AMP 579. Further experiments determined the effects of AM P 579 when administered 30 min after the onset of myocardial ischem ia, 10 min before reperfusion. Two doses were studied: a low hemodynam ically silent dose (3 mu g/kg + 0.3 mu g/kg/min through 1 hr of reperf usion) and a 10-fold higher dose that did cause reductions in blood pr essure and HR. Both doses of AMP 579 produced a comparable cardioprote ctive effect, reducing infarct size to approximately 50% of that obser ved in control animals. The cardioprotective effect of AMP 579 was a c onsequence of adenosine receptor stimulation, because it was completel y inhibited by pretreatment with the specific adenosine receptor antag onist CGS 15943 (1 mg/kg i.v.). However, the selective A, receptor ago nist GR 79236 (3 mu g/kg + 0.3 mu g/kg/min i.v.) did not reduce infarc t size, which suggests that under these experimental conditions, stimu lation of adenosine A, receptors is important for the cardioprotective effect of AMP 579. The adenosine-regulating agent acadesine (5 mg/kg + 0.5 mg/kg/min i.v.) also failed to reduce infarct size. In conclusio n, the novel adenosine A(1)/A(2) receptor agonist AMP 579 produces mar ked cardioprotection whether administered before myocardial ischemia o r reperfusion. Cardioprotection is not dependent on changes in afterlo ad or myocardial oxygen demand and is a consequence of adenosine recep tor stimulation. The pharmacological profile of AMP 579 in this model is consistent with its potential utility in the treatment of acute myo cardial infarction.